Childhood cancer is rare, with only approximately 10,000 new cases diagnosed each year in the United States. Nonetheless, cancer is the leading cause of disease-related mortality in children younger than 15 years of age.¹ Pediatricians and general practitioners commonly encounter children with vague symptoms that could signal an undiagnosed cancer. The challenge is to identify those children who warrant an evaluation for malignancy. This chapter reviews the typical presentations of the most common pediatric hematologic and solid tumors and provides guidelines for the initial diagnostic evaluation. A review of current therapies and expected outcomes is beyond the scope of this chapter. However, it can be broadly stated that the majority of children diagnosed with cancer can be cured of their disease with currently available treatment.

Cancer results from the uncontrolled proliferation of a clonal cell population, and can arise in essentially any cell type or organ. In general, children with cancer present with symptoms related to the location and extent of the tumor. Cancers cause symptoms by invading or obstructing tissues locally or by spreading to distant sites, leading to pain, organ dysfunction, or both. During childhood, the incidence of specific malignancies varies dramatically with age. The most common types of cancer in children are hematologic malignancies (i.e. leukemias, lymphomas), brain tumors, and extracranial solid tumors, including sarcomas and embryonal tumors.

Because childhood cancer is rare and heterogeneous, the elucidation of its causes is extremely challenging. Certain factors are associated with an increased risk of some types of childhood cancer. For example, in utero exposure to ionizing radiation leads to about a 1.5-fold increased risk of lymphoblastic leukemia.² External beam radiation, sometimes used to treat patients with solid tumors, is associated with an increased risk of osteosarcoma within the radiation field. Patients with Down syndrome have a 10- to 20-fold increased risk of developing leukemia.³ Several other genetic syndromes are also associated with an increased risk of developing cancer, including neurofibromatosis, Beckwith-Wiedemann syndrome, and Li-Fraumeni syndrome (Table 132-1). However, in the vast majority of children with cancer, no predisposing factors are identified.

The incidence of childhood cancer is highest in the first year of life, declines until about age 9 years, and then gradually increases into adulthood. The peak rates of specific childhood malignancies occur at different ages. In a child with suspected cancer, the age at presentation has a major impact on the differential diagnosis.

Leukemia accounts for approximately one-third of cancers diagnosed in childhood. In contrast to adults, acute lymphoblastic leukemia (ALL) occurs relatively more commonly than acute myeloid leukemia (AML). In fact, ALL is the most common specific childhood malignancy, representing approximately 20% of cancers diagnosed in children younger than 15 years. The peak age at diagnosis of childhood ALL is 2 to 3 years. White children are about two times more likely than black children to be diagnosed with ALL, and boys are affected slightly more commonly than girls. In contrast, the incidence of AML peaks in the first year of life, subsequently decreases, and then gradually increases late in childhood and throughout adulthood. Chronic leukemias are distinctly uncommon in childhood. Chronic myeloid leukemia accounts for only about 3% to 5% of childhood leukemia cases and chronic lymphoid leukemia does not typically occur in children. Non-Hodgkin lymphoma (NHL) accounts for 3% of cancers diagnosed in children, and Hodgkin lymphoma accounts for about 5%.

Brain tumors are a diverse group of malignant neoplasms that, taken together, account for approximately 30% of childhood cancers.

Among pediatric solid tumors that originate outside the central nervous system, neuroblastoma is the most common, representing 8% of childhood cancers, primarily affecting children younger than 5 years. Wilms tumor accounts for 6% of childhood cancers and also occurs primarily in those younger than 5 years. The bone sarcomas, including osteosarcoma and Ewing sarcoma, together represent 5% of childhood cancers. These tumors generally affect older children, with the highest incidence in adolescence and young adulthood.

LEUKEMIA

Clinical Presentation and Differential Diagnosis

ALL arises as a consequence of malignant transformation of lymphocyte precursors in the bone marrow or lymphoid organs.⁴ AML is an analogous process involving malignant transformation of myeloid progenitors.⁵ The presentation of new-onset leukemia may be dramatic, insidious, or rarely even asymptomatic, with an incidental finding of leukemia blasts on peripheral blood smear. Often, the differential diagnosis includes benign conditions, such as acute viral infection (e.g. Epstein-Barr virus), aplastic anemia, hemophagocytic syndrome, and other rare congenital disorders (Table 132-2).

Children with new-onset acute leukemia usually present with symptoms caused by the impaired production of normal blood cells, owing to the proliferation of leukemia cells in the bone marrow. Fatigue, pallor, and fever are common presenting symptoms. Decreased numbers of normal white blood cells lead to an increased risk of serious infection. Bruising and petechiae may be present due to thrombocytopenia. Concomitant coagulopathy may magnify the risk of serious bleeding, especially in certain leukemia subtypes. Patients may complain of bone pain or present with limp or refusal to walk related to bone marrow infiltration and expansion. Leukemia cells may infiltrate organs such as the lymph nodes, liver, or spleen, resulting in lymphadenopathy or hepatosplenomegaly. Leukemia cells may form solid masses, such as in the anterior mediastinum, leading to tracheal or vascular compression. Uncommonly, new-onset leukemia involves the central nervous system, testes, skin, gingivae, and eyes. Children with very large numbers of circulating malignant cells (white blood cell counts >200,000/μL) may experience symptoms of hyperleukocytosis with ocular, neurologic or respiratory symptoms (see Chapter 133). Hyperleukocytosis occurs in patients with AML at relatively lower white blood cell counts than in ALL.

Diagnostic Evaluation and Management

When leukemia is suspected, immediate evaluation is warranted, beginning with a complete blood count. The white blood cell count may be low, normal, or elevated. Leukemia blasts may be seen in the peripheral blood smear. Anemia with reticulocytopenia and thrombocytopenia are usually present but of variable severity. When leukemia is strongly suspected, it is important to assess renal function and serum electrolytes, including calcium, phosphate, and uric acid. Patients with a large, rapidly proliferating leukemia burden may present with features of acute tumor lysis syndrome (see Chapter 133) even before the initiation of cytotoxic therapy. Liver function tests should also be performed because marked elevation of lactate dehydrogenase is often seen and hyperbilirubinemia may be present. Coagulation studies should be obtained, and coagulation abnormalities should be corrected before high-risk invasive procedures are attempted, including lumbar puncture and central line placement. Blood cultures should be obtained from patients presenting with fever, and empirical antibiotics should be strongly considered, especially if the neutrophil count is low. A blood sample should be sent to the blood bank in preparation for red blood cell or platelet transfusion. A screening chest radiograph is also recommended. Intravenous access should be established and the patient should be hospitalized for completion of the diagnostic evaluation and initiation of therapy.

Further diagnostic workup should then be performed under the direction of a hematologist/oncologist. Expert evaluation of the peripheral blood smear is often informative (Figure 132-1). When circulating blasts are present, flow cytometry of peripheral blood may establish the diagnosis. Examination of the bone marrow is needed to complete the evaluation of morphology, flow cytometry, and cytogenetic and molecular analysis. These studies have become increasingly important for risk stratification in patients with ALL and AML. In most cases, assessment of the cerebrospinal fluid by lumbar puncture is performed to document the presence or absence of leukemic involvement. At the time of the initial staging lumbar puncture, chemotherapy should be instilled directly into the spinal fluid. Diagnostic lumbar puncture without intrathecal chemotherapy is strongly discouraged.

NON-HODGKIN LYMPHOMA

Clinical Presentation and Differential Diagnosis

Several different subtypes of NHL occur in childhood,⁶ the most frequently encountered types demonstrating high-grade histology and aggressive behavior. Lymphoblastic lymphoma is a malignant lymphoma that is indistinguishable from ALL except that the extent of bone marrow involvement is, by definition, less than 25%. Most cases of lymphoblastic lymphoma are of precursor T-cell origin. Children with lymphoblastic lymphoma often present with an anterior mediastinal mass (Figure 132-2). Compression of the airway or vascular structures at or below the thoracic inlet can lead to orthopnea or superior vena cava syndrome. Diagnosis is made by means of biopsy of involved tissue. When a mass is present in the anterior mediastinum, biopsy requires extreme caution owing to the high risk of anesthesia in the setting of tracheal compression.

Burkitt lymphoma is a high-grade malignancy of mature B-cell origin. In the United States, the disease occurs in a sporadic form, with the majority of tumors presenting in the abdomen. Bone marrow or central nervous system involvement is relatively uncommon and is associated with a less favorable prognosis.⁷ Because of the extremely rapid growth rate of this tumor, patients are at high risk for the development of hyperuricemia and acute tumor lysis syndrome at presentation and after initiation of treatment.

Large-cell lymphomas may be of B-cell, T-cell, or null-cell origin. These tumors arise most commonly in the lymph nodes of the mediastinum and abdomen but may arise in or spread to skin, bone, and soft tissues.

Diagnostic Evaluation and Management

The same laboratory assessment described above for leukemia, including measurement of electrolytes, creatinine, and uric acid, is recommended for all patients with suspected or confirmed NHL. Diagnosis depends on histopathologic examination of tumor tissue. Sufficient biopsy material should be obtained so that specialized flow cytometric and molecular studies can be performed. These studies may demonstrate specific molecular characteristics that define certain tumor types, such as rearrangement of the MYC oncogene in Burkitt lymphoma. Computed tomography (CT) of the chest, abdomen, and pelvis, fluorodeoxyglucose positron emission tomography (FDG-PET) scan and examination of the bone marrow and cerebrospinal fluid are usually performed to determine the stage of the disease. Because systemic therapy is necessary in nearly all cases of lymphoma, an aggressive attempt at complete surgical resection is usually not warranted.